title: Validation of tumour models for use in anticancer nanomedicine evaluation: the EPR effect and cathepsin B-mediated drug release rate.
abstract: OBJECTIVE
  Intravenously (i.v.) administered nanomedicines have the potential for tumour targeting due to the enhanced permeability and retention (EPR) effect, but in vivo tumour models are rarely calibrated with respect to functional vascular permeability and/or mechanisms controlling intratumoural drug release. Here the effect of tumour type and tumour size on EPR-mediated tumour localisation and cathepsin B-mediated drug release was studied.
  
  
  METHODS
  Evans Blue (10 mg/kg) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer–doxorubicin (Dox) conjugate (FCE28068) (5 mg/kg Dox-equiv) were used as probes and tumour levels (and Dox release) measured at 1 h after i.v. administration in a panel of murine and human xenograft tumours.
  
  
  RESULTS
  Evans Blue and FCE28068 displayed similar tumour levels in the range of 2–18 % dose/g at 1 h for B16F10 and L1210. Approximately half of the tumour models evaluated exhibited tumour size-dependent accumulation of FCE28068; smaller tumours had the highest accumulation. Administration of free Dox (5 mg/kg) produced tumour levels of \2.5 % dose/g independent of tumour size. Whereas the degree of EPR-mediated targeting showed *12-fold difference across the tumour models evaluated, Dox release from FCE28068 at 1 h displayed *200-fold variation.
  
  
  CONCLUSIONS
  Marked heterogeneity was seen in terms of EPR effect and Dox release rate, underlining the need to carefully calibrate tumour models used to benchmark nanomedicines against known relevant standard agents and for optimal development of strategies for late pre-clinical and clinical development.
authors.affiliation: Centre for Polymer Therapeutics, The School of Pharmacy, 29-39 Brunswick Square, London, UK. profruthduncan@btinternet.com
authors.forename: Ruth
authors.initials: R
authors.lastname: Duncan
authors.forename: Yee-Nee
authors.initials: YN
authors.lastname: Sat-Klopsch
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Burger
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bibby
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Fiebig
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002401:Cathepsin B / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004396:Coloring Agents; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005070:Evans Blue; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D036103:Nanotechnology; D010539:Permeability; D011099:Polyglutamic Acid; D011108:Polymers; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004396:Coloring Agents; D003692:Delayed-Action Preparations; D011108:Polymers; C482378:N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate; D011099:Polyglutamic Acid; D005070:Evans Blue; D004317:Doxorubicin; D002401:Cathepsin B